Systemic Retinoids

General Aspects

The metabolism of retinoids is mainly via oxidation and chain shortening to biologically inactive, water-soluble products in the liver. The oxidative metabolism is induced mainly by retinoids themselves, and possibly also by other agents known to induce hepatic cytochrome P-450 (CYP) 3A4 isoform.

There are important differences in the terminal elimination half-lives ( T _1/2 ) among the three generations of retinoids. Q22.2 Tretinoin has the shortest half-life, at 40 to 60 minutes, followed by bexarotene at 7 to 9 hours, then isotretinoin at 10 to 20 hours, then acitretin at 50 hours. Etretinate has a prolonged half-life of 80 to 160 days. After etretinate therapy is discontinued, the serum concentrations quickly drop to very low levels; however, these levels may persist for up to 2.9 years. Both isotretinoin and acitretin are completely cleared from the body within 1 month after the drug is stopped. Based on short T _1/2 values, bexarotene probably has a clearance profile similar to isotretinoin.

All four drugs are excreted in the urine and feces. Glucuronide conjugated metabolites appear in the bile with subsequent excretion in the feces.

Acitretin Re-esterification (Reverse Metabolism)

Q22.2 Alcohol indirectly enhances the re-esterification of acitretin to etretinate, which is detectable only after a few days of an acitretin regimen. Following 3-month administration of acitretin (30 mg/day) in 10 patients with psoriasis, steady-state plasma etretinate concentrations were detected at 2.5 to 56.7 ng/mL. In another two-way crossover study, all 10 subjects formed etretinate with concurrent ingestion of a single 100 mg dose of acitretin during a 3-hour period of ethanol ingestion. The formation of etretinate in this study was comparable to a single 5-mg oral dose of etretinate. In another study of 86 patients with at least 4 consecutive weeks of acitretin exposure, 30 were found to have detectable plasma etretinate levels. No etretinate was detected in the 20 patients who reported that they never drank alcohol, whereas etretinate was found in all 16 patients with an average weekly alcohol consumption of 15 drinks. Etretinate was detected in 14 of 50 patients with more moderate weekly alcohol.

Based on these data, the recommended period for contraception after acitretin therapy has been lengthened from 2 months to 2 years in Europe. In the United States, the recommended period for contraceptive use after cessation of acitretin is even longer, at 3 years.

A study of 37 women of childbearing age exposed to acitretin evaluated the levels of detectable etretinate concentration in 20 women who still used acitretin, and in 17 women who stopped therapy for up to 29 months. This study revealed the prevalence of detectable etretinate concentrations to be respectively 45% and 83% in plasma and subcutaneous tissue, among current acitretin users and 18% and 86% among those who had stopped acitretin therapy. In another study, after 4 to 11 months of treatment with etretinate, its concentration in the subcutaneous fat attained equilibrium at a level of about 100 times that in plasma. Even though the drug concentrations in the fat compartment are much higher than those in serum or skin tissue, it is unknown whether these persistent levels are truly sufficient for toxicity. Regardless, inability to detect plasma etretinate is a poor predictor of the absence of etretinate in fat.

Transport of Retinoids

Physiologically, RA is predominantly in the all- trans form (ATRA). A small fraction is transported as 13- cis RA. Serum transport is by albumin. The intracellular carrier known as cytosolic retinoic acid-binding protein ( CRABP ) exists in two isoforms, CRABPI and CRABPII, and transports RA to the cell nucleus.

CRABP is present in high levels in the epidermis, and is markedly elevated in lesional skin of psoriasis (by 800% compared with nonlesional skin), lamellar ichthyosis, lesional Darier disease, pityriasis rubra pilaris, and keratosis pilaris. High levels of CRABP might indicate a greater sensitivity of the lesions to retinoids.

Mechanism At the Nuclear Level

Retinoids exert their physiologic effects by binding to receptors present in the nucleus ( Table 22.3 ). Q22.3 There are two families of retinoid receptors, a retinoic acid receptor (RAR) family and a retinoid X receptor (RXR) family, each having three isoforms (α,β, and γ) encoded by separate genes. RAR are always paired with an RXR, whereas RXR can exist as a homodimer with another RXR, or as a heterodimer with several other families of receptors, such as vitamin-D ₃ receptor, thyroid hormone receptor, and peroxisome proliferator-activated receptor. Retinoid receptors belong to the large superfamily of receptors consisting also of glucocorticosteroid, thyroid hormone, and vitamin-D ₃ receptors, all of which are deoxyribonucleic acid (DNA)-binding proteins and functioning as trans -acting transcription modulating factors.

The genes regulated by retinoids contain a retinoic acid response element (RARE), which is a DNA sequence to which the RAR-RXR heterodimer binds. Upon binding of a ligand, the RAR-RXR heterodimer acts a transcription factor, resulting in the expression of a number of proteins involved in growth and regulation. The retinoid-receptor complex can also act in an indirect fashion by antagonizing the action of other transcription factors, specifically activating protein 1 (AP-1). The clinical effects of systemic retinoids in dermatology are related to their ability to affect pathways involved in inflammation, cellular differentiation, apoptosis, and sebaceous gland activity. In addition to their actions on the skin, retinoids exert broad effects in multiple tissues, a complete description of which is beyond the scope of this chapter.

Psoriasis—Retinoids As Monotherapy

After etretinate was removed from the market in 1998, owing to concerns about its long half-life, it was replaced by acitretin, which remains the only systemic retinoid to receive FDA approval for the treatment of psoriasis. Multiple studies have demonstrated acitretin’s effectiveness when used as monotherapy for the treatment of psoriasis. When different doses of acitretin were evaluated, higher doses (50 and 75 mg) were found to be more effective than lower doses (10 and 25 mg). A retrospective analysis was performed on two of these studies, demonstrating Psoriasis Area and Severity Index (PASI)-50 and PASI-75 response rates in more than 76% and 46% of patients, respectively, at an average daily dose of 41 mg. Clinical experience has shown that acitretin monotherapy in chronic plaque psoriasis often leads to decreased thickness, scaling, and itching of the plaques, without reducing the body surface area involved. Patients should also be aware that whereas the initial clinical effects are often seen in 4 to 6 weeks, it may take up to 3 to 4 months or longer to see the full clinical benefits.

Analysis of 385 cases of generalized pustular psoriasis (GPP) revealed that retinoid treatment was effective in 84% of patients, methotrexate in 76% of patients, cyclosporine CsA in 71% of patients, and oral psoralen plus ultraviolet A (PUVA) in 46% of patients. Localized pustular psoriasis of the palms and soles also responds very well to retinoid therapy.

The optimal dosing strategy for acitretin therapy appears to be initiation at a dose of 25 mg daily and increasing the dose based on effectiveness and/or patient tolerance. Once satisfactory control of the disease is reached, attempting to reduce the acitretin dose to 10 mg daily or 25 mg every other day is a reasonable plan for long-term maintenance.

Psoriasis—Retinoids in Combination Therapy

Q22.4 Combination therapy with systemic retinoids and phototherapy is more effective than monotherapy with either modality. In addition, combination therapy reduces the long-term risks associated with ultraviolet light (photoaging, skin cancer) by reducing the cumulative UV doses necessary for an adequate clinical response to phototherapy.

Acitretin with broadband UVB (ReUVB) has been evaluated in randomized, controlled studies. Both of these studies demonstrated significant improvement in patients receiving acitretin plus UVB therapy compared with patients receiving UVB therapy alone, with significantly shorter total treatment times and UVB doses in the patients receiving acitretin. Similar findings were also seen in patients receiving narrowband UVB and acitretin. Acitretin with PUVA (RePUVA) has been shown in formal studies to improve the efficacy of PUVA, while reducing the PUVA dose required for clearance. Acitretin at a dose of 25 mg daily has also been evaluated in combination with commercial tanning bed therapy, which demonstrated PASI-50 and PASI-75 response rates in 76% and 59% of patients, respectively.

Current recommendations for combination acitretin-UV therapy include instituting low-dose (25 mg) acitretin, 2 weeks before the initiation of phototherapy. If skin-type dosing is used, the initial dose of UV light and subsequent increments should be adjusted downward to accommodate the acitretin effect. Alternatively, if a patient is on a stable dose of UV, the UV dose should be lowered by 30% to 50% approximately 7 days after starting acitretin.

Acitretin can be used in combination with methotrexate or cyclosporine in specific situations; however, every attempt should be made to limit the time period for which patients are taking both medications because of potential adverse liver effects with the acitretin-methotrexate combination and possible elevations in serum triglycerides that may occur with patients taking both acitretin and cyclosporine. Close laboratory monitoring of the aforementioned combinations of systemic medications is of great importance.

One specific setting, in which combination therapy is effective, is a ‘sequential regimen,’ which can be used at the onset of therapy (see Chapter 17 on cyclosporine). In this setting, a rapidly effective agent, such as cyclosporine, is instituted initially. Once the patient has responded to the cyclosporine, this drug is tapered off over 3 to 4 months, while an agent with better long-term safety, such as acitretin, is added. This type of sequential regimen takes advantage of cyclosporine’s rapid onset of action and acitretin’s excellent long-term safety profile.

Retinoids in Combination with Biologic Agents

Because retinoids are generally not considered to be immunosuppressive, they may be considered ideal candidates for combination therapy with the biologic agents, and there is an increasing body of evidence to support the benefits of this combination. In a randomized trial comparing etanercept 25 mg twice weekly, acitretin 0.4 mg/kg daily, and the combination of etanercept 25 mg once weekly and acitretin 0.4 mg/kg daily, the combination of acitretin with etanercept 25 mg once weekly was superior to acitretin alone and was equivalent to etanercept 25 mg twice weekly, with similar safety profiles. However, randomized studies of acitretin in combination with other biologic agents are lacking.

Acne Vulgaris

The only systemic retinoid that is FDA approved for the treatment of acne is isotretinoin. Current FDA guidelines state that isotretinoin is approved for the treatment of severe recalcitrant nodular acne. ‘Recalcitrant nodular acne’ is defined by the FDA as inflammatory lesions larger than 5 mm in diameter and unresponsive to conventional therapy, including systemic antibiotics. ‘Severe,’ in this context, is defined as ‘many’ lesions (as opposed to ‘few’ or ‘several’). In view of this narrow definition that would limit the use of isotretinoin to very select patients, some have suggested that the indications be expanded. A recent consensus conference defined severity in terms of the impact of the disease on the patient, not on the number of lesions. The first available version of isotretinoin, marketed as Accutane, was withdrawn from the US market in 2009, but several other forms of isotretinoin are still available on prescription in the United States (see Table 22.1 ).

The first report documenting the effectiveness of isotretinoin for the treatment of acne demonstrated 100% improvement in 13 of 14 patients given the medication at an average dose of 2 mg/kg daily for 4 months. The same authors subsequently conducted a randomized placebo-controlled trial confirming the dramatic effect of isotretinoin in treating acne, along with evidence of a long-term decrease in sebaceous gland size and sebum production. Q22.5 In a dose-comparison study comparing 0.1, 0.5, and 1.0 mg/kg daily for 20 weeks, clinical improvement was essentially the same for all three groups at the end of 20 weeks, with a higher percentage of patients requiring retreatment in the 0.1 mg/kg daily group. A retrospective study confirmed a higher relapse rate with lower doses. In this study, 82% of patients who had received 120 mg/kg cumulative dose relapsed, compared with just 30% of patients who received a larger cumulative dose of 150 mg/kg. Another study suggested that a cumulative dose of greater than 220 mg/kg should be used as a target owing to rates of relapse that were lower than patients who received a cumulative dose less than this (rates of relapse, 26.9% vs. 47.4%, respectively). Despite the lack of rigorous scientific evidence, an isotretinoin dose in the range of 0.5 to 1.0 mg/kg daily, until a total cumulative dose of 120 to 150 mg/kg is reached, seems to be a reasonable therapeutic plan in most patients, with the understanding that ideal cumulative doses for individual patients may vary and may depend on baseline acne severity.

In terms of practical issues, patients should understand that their complexion may worsen for the first 4 to 6 weeks of isotretinoin therapy, after which time they are likely to see improvement over the next few months, so that during the fourth and fifth months of therapy, many patients are clear or almost clear. Patients should also understand that if their acne does relapse, it is very likely that it will be much more responsive to conventional therapy following the course of isotretinoin. If a second course of isotretinoin is necessary, the rate of success (clearance without relapse) is similar to that seen with initial courses, that is, approximately 70%. Although formal guidelines are lacking, waiting at least 2 to 3 months after the initial course, before initiating a second course of isotretinoin, is reasonable given that isotretinoin improvement may continue at least a couple months after drug cessation.

Cutaneous T-Cell Lymphoma—Mycosis Fungoides and Sézary Syndrome

In 1999 the FDA approved bexarotene for the treatment of the cutaneous manifestations of CTCL in patients who were refractory to at least one previous systemic therapy. Two open-label Phase II-III trials (treating predominantly mycosis fungoides) demonstrated overall response rates of 48%, with a complete response rate of 4%, in patients who were taking 300 mg/m ² daily, which was determined to be the optimal dose of bexarotene balance effectiveness and toxicity. The mechanism of action of bexarotene in CTCL has not been fully elucidated, although two studies have suggested that apoptosis of the malignant T cells is induced. An algorithm has been proposed for the use of bexarotene in the management of CTCL which addresses the dose, the response to therapy, and AE of bexarotene (see later).

Rosacea

Compared with acne, rosacea tends to be a more chronic disease that frequently flares when systemic therapy is discontinued. For this reason, low-dose isotretinoin has been studied for rosacea, with doses of 10 mg/day demonstrating effectiveness in treating telangiectasia, erythema, and papules and pustules. One study comparing the treatment of rosacea with isotretinoin, at doses of 0.1, 0.3, and 0.5 mg/kg daily with doxycycline 100 mg twice daily, found that isotretinoin at 0.3 mg/kg daily was as effective as doxycycline, with a similar safety profile. Continuous ‘microdoses’ as low as 20 to 30 mg per week, after low daily doses of isotretinoin for 4 to 6 months, also prevented relapses in rosacea patients. However, with the requirements of the iPledge system, the long-term low-dose use of isotretinoin has become more challenging.